Association between social jetlag and chronic kidney disease among the Korean working population

Social jetlag refers to the discrepancy between social time and the body’s internal rhythm, which can lead to unfavorable health outcomes. However, no study has directly explored the relation between social jetlag and chronic kidney disease (CKD). This study aims to investigate the relationship between social jetlag and CKD in a representative population of South Korea. This study included 8259 currently economically active Korean population in the Korea National Health and Nutrition Examination Survey. Social jetlag was calculated as the difference between the midpoint of sleep time on weekdays and free days. The estimated glomerular filtration rate (eGFR) was calculated the by using the serum creatinine value according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Participants with an eGFR less than 60 ml/min/1.73 m2 were defined as CKD cases. The estimated glomerular filtration rate decreased as social jetlag increased. Multiple logistic regression analysis showed that the adjusted odds ratio (95% confidence interval) of CKD for 1–2 h of social jetlag was 0.926 (0.660–1.299), while the odds ratio for more than 2 h was 2.042 (1.328–3.139) when less than 1 h was used as reference. This study found that social jetlag and risk of CKD were significantly related in the Korean working population.

Social jetlag. Social jetlag conditions were measured using questions about typical sleep-onset and wake times on weekdays and weekends. In addition, the midpoint of sleep was evaluated as the midpoint of the sleep start time (adding sleep latency time before sleep) and the wake time.
The midpoint of sleep time was then calculated separately for the weekdays (midpoint of sleep time on a weekday [MSW]) and weekend or free days (midpoint of sleep time on free days [MSF]). According to the formula established by Wittman et al. 10 , social jetlag was estimated as the absolute value of the difference (in hours) between the midpoints of sleep times on weekdays and weekends (MSF-MSW). In this study, the social jetlag of 98% of the participants was between − 0.75 and 3.75 h. Therefore, we classified the participants into the following three groups: less than + 1 h, + 1 to less than + 2 h, and more than + 2 h of social jetlag. The reference category was less than 1 h, as reported previously 20,21 . Assessment of kidney function. In fasting blood samples (12-h overnight), obtained through antecubital venipuncture, the serum creatinine level was measured using the Hitachi Automatic Analyzer 7600 (Hitachi, www.nature.com/scientificreports/ Tokyo, Japan) and CREA reagent (Roche Diagnostics, Mannheim, Germany). We calculated the estimated glomerular filtration rate (eGFR) by using the serum creatinine value according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation that, across a broad range of populations, more accurately categorizes the risk for mortality and ESRD than does the Modification of Diet in Renal Disease (MDRD) study equation 22 . Participants with an eGFR less than 60 ml/min/1.73 m 2 were defined as CKD case 23 .
Other variables. Household income was used to measure income levels because they could be an indicator of an individual's material resource status, especially in women who may not be the primary household income earners 24 . Therefore, we used the equivalized household income (EHI), which was calculated as the gross household income divided by the square root of household size. Accordingly, the participants were classified into four groups (low, low-middle, middle, and high). Marital status was classified into three groups: married, unmarried, and other (about to be wedded, separated, or divorced). We used additional variables, such as education level (elementary school, middle school, high school, and ≥ college), occupation (white collar, blue collar, pink collar, or others), smoking habits (non-smoker, current smoker, or ex-smoker), drinking problem (yes or no), and selfrated health (fair or poor). The underlying diseases, such as hypertension and diabetes, were determined based on the self-reported information of the disease that had been diagnosed by doctors.

Results
The characteristics of the participants according to their social jetlag categories are presented in Table 1. The proportion of those with < 1, 1-2, and > 2 h of social jetlag was 63.80, 25.67, and 10.53%, respectively. The prevalence of 2 h of social jetlag was higher in those who are of younger age, are unmarried, highly educated, current smokers or problem drinkers than others. As shown in Fig. 2, the result of GAM with smoothing spline function indicated that the eGFR decreased as social jetlag increased when the difference in the midpoint of sleep times between weekdays and weekends (MSF − MSW) was a positive value. A total of 338 (4.09%) participants were identified as CKD. The Crude ORs of CKD among the 1-2 h and > 2 h social jetlag groups in Model 1, with the < 1 h group as a reference, were 0.543 (95% CI = 0.395-0.749) and 0.886 (95% CI = 0.603-1.300), respectively (Table 2). However, this association was significantly reversed in the model with analyses adjusted for age and sex. The ORs for the groups with 1-2 h and > 2 h social jetlag were 0.908 (95% CI 0.649-1.268), and 2.234 (95% CI 1.473-3.387) in Model 2, respectively. In the model that was further adjusted for marital status, occupation, weekly work hours, smoking, drinking, hypertension, diabetes, and self-rated health, the ORs were significantly higher among the groups with social jetlag of > 2 h than the group with social jetlag of < 1 h (OR = 2.042, 95% CI 1.328-3.139).
In the subgroup analysis (Table 3), male sex, the highest income groups, those who did not work long hours, those without diabetes, and those with obesity or poor self-rated health showed relatively higher OR of CKD related with social jetlag, and there were dose-response relationships in these subgroups. However, some associations were not significant.

Discussion
This study observed the linking between social jetlag and the CKD, particularly among middle-aged or older workers. Although statistically significant association between social jetlag and CKD was not determined in unadjusted models, the association between social jetlag > 2 h and CKD was observed in the adjusted models 1 and 2. Model 2 included sex and age, whereas Model 3 additionally included occupation, marital status, weekly working hours, smoking, drinking, hypertension, diabetes, and self-rated health. This may be due to the fact that, despite social jetlag being more prevalent among younger workers, its deleterious impact on the kidney is more pronounced among workers in their fifties. As seen in subgroup analysis, social jetlag showed greater association with CKD among certain subgroups of workers (e.g., those not working long hours, those without diabetes, those with obesity, and those with poor self-rated health).
Several plausible mechanisms might explain the relationship between social jetlag and CKD. Social jetlag is a form of circadian misalignment 12 , and it may lead to insufficient sleep duration, poor sleep quality, and insufficient recovery 26  www.nature.com/scientificreports/ CKD. In the suprachiasmatic nucleus(SCN) central circadian clock is located (SCN) and many peripheral organs show circadian rhythmicity 27 . Furthermore, renal function is regulated by the circadian pattern, and includes glomerular filtration, which oscillates in accordance with the circadian clock 28,29 . The circadian clock affects various levels of cellular function, including transcription, translation, and post-translational changes 30,31 . In the present analysis, the eGFR showed decreasing trend in the generalized additive model as the duration of the social jetlag increased. Misalignment of the circadian clock is related to CKD progression in animal models 32 . Shift work, another type of circadian misalignment in a significant proportion of the working population, increases the risk of chronic kidney dysfunction 7,33 . Another possible contributor may be the insufficient sleep duration of workdays and low sleep quality. Insufficient sleep duration and low sleep quality are closely related to CKD or proteinuria [34][35][36] . The findings of previous studies showed some similarity with the result of this study, and they provided indirect evidence of findings of this study. Insufficient recovery due to social jetlag may decrease renal function. In addition, long work hours are associated with CKD and can lead to insufficient recoveries, like social jetlag 8,37 . Further explorations are required on mechanisms of social jet lag and health.
The strength of the current study is the use of a nationally representative sample of the Korean working population. However, since this study is a cross-sectional study, the temporal sequence of the exposure and health status and the causal inference cannot be verified. For this reason, there is a possibility of reverse causation, in that CKD may influence sleep and chronotype. The future prospective cohort study can clarify the causal direction between social jetlag and CKD. Another limitation of the present study is the operational definition of CKD. CKD is defined as the existence of structural or functional abnormalities in the kidneys that persist for at least three months 1 . However, due to the nature of the study design, we used only a single measurement of eGFR. This may lead to information bias as well as an overestimation of the prevalence of CKD. Also, other potential confounding, such as various causes of CKD, were not sufficiently considered, except for hypertension and diabetes. Moreover, the KNANES did not investigate information on renal disease morbidity, including glomerulonephritis, and could not exclude them from the study population. For this reason, selection bias may Figure 2. Nonparametric association between social jetlag (hours) and standardized estimated glomerular filtration rate (mL/min/1.73 m 2 ) that was adjusted for age, sex, marital status, occupation, weekly working hours, smoking, drinking, hypertension, diabetes, obesity, and self-rated health. Note that the y-axis is "difference from the mean", not the actual value of estimated glomerular filtration rate. Table 2. Risk of chronic kidney disease according to the categories of social jetlag. a Crude odds ratio was calculated by logistic regression. b Adjusted odds ratio was calculated by multiple logistic regression analysis after adjusting for age and sex. c Adjusted odds ratio was calculated by multiple logistic regression analysis after adjusting for age, sex, marital status, occupation, weekly working hours, smoking, drinking, hypertension, diabetes, obesity, and self-rated health. www.nature.com/scientificreports/ influence the results of the current study. Finally, sleep and wake times were self-reported, which may have resulted in information bias. Objective measurement of sleep time, such as actigraphy can reduce measurement errors by using subjective reports of sleep time.
In conclusion, social jetlag was associated with reduced eGFR among the general working population in Korea. To reduce CKD in the working population, workplace interventions may be needed to reduce the influence of social jetlag. For example, it is possible that a work schedule that employees have some level of control over, Table 3. The risk of chronic kidney disease according to the categories of social jetlag by subgroup a . a Adjusted odds ratio was calculated by multiple logistic regression analysis after adjusting for age, sex, marital status, occupation, weekly working hours, smoking, drinking, hypertension, diabetes, obesity, and self-rated health. b Widowed, separated, or divorced. c Workers in the agriculture, forestry, fishery, and military sectors. d Gross household income was divided by the square root of household size.